This is a competing renewal of the Penn State College of Medicine RMN Unit. We have contributed significantly to the productivity of the RMN in the prior funding cycle as a major recruiting site and developer of protocols. Dr. Legro's concept protocol from that cycle was prioritized as the first study to be undertaken, and he became the Lead Investigator of the completed Pregnancy in Polycystic Ovary Syndrome Study (PPCOS), as well as a pharmacogenetic addendum. These findings will have a marked impact on the treatment of women with PCOS. The University and Department have strengths in reproductive and clinical research that enhance the RMN unit at this site. Additionally clinical programs in the surgical and medical treatment of female and male infertility are well established and interlinked. Laboratories dedicated to reproductive medicine (assisted reproductive technologies, andrology, and reproductive endocrinology) and an NIH-supported Clinical Research Center enhance the clinical and research programs. The proposed administrative structure for the RMN Unit includes a Principal Investigator, Richard S. Legro, M.D. Director of the Division of Reproductive Endocrinology Research, A Co-Investigator with expertise in Male Infertility, J.C. Trussell, from the Division of Urology, and a Biostatistician with expertise in statistical genetics, Gary Chase, Ph.D, from the Department of Health Evaluation Sciences. In this cycle we plan to complete ancillary studies and sub-analyses from the PPCOS study as well as materially contribute to all new protocols and we anticipate that the redesigned RMN will now be able to conduct multiple protocols concurrently. We propose a concept protocol, which builds on the findings and experience garnered in PPCOS, and propose a double blind randomized two armed trial of clomiphene citrate vs. letrozole in infertile women with PCOS to establish superiority in terms of the primary outcome of live birth as well as to delineate the safety profile of the two drugs. We will also explore secondary important outcomes such as multiple pregnancy, abortion rates, pregnancy complications, and predictive factors including candidate response gene alleles. These studies are essential to establishing safe and efficacious treatments for anovulatory infertility, contributing to understanding of response mechanisms, and realistically are only likely to be conducted with the support of NIH given the involvement of pregnant women and fetuses. [unreadable] [unreadable] [unreadable]